Conventionally 3-alkoxymethylcephem derivatives represented by the formula (II) are prepared by a common process disclosed in J. Antibiot., XL, 370(1987) and represented by the following reaction scheme, i.e., by reacting thionyl chloride with a 3-hydroxymethylcephem derivative to obtain a chloride, iodizing the chloride, and reacting the resulting iodide with an alcohol in the presence of mercury nitrate. This process requires the use of hazardous reagents such as thionyl chloride and mercury nitrate for the reactions and is in no way a practical process. ##STR3## wherein R.sub.1, R.sub.3 and R.sub.4 are the same as defined later.
J. Chem. Soc. PERKINTRANS. I, 2281(1983) and Helvetica Chimica Acta, 58, 2469(1975) disclose a process for preparing the derivative from a 3-brominated methylcephem compound or 3-fluorinated methylcephem compound by a substitution reaction in an alcohol, whereas this process is far from being feasible since the starting material, i.e., 3-brominated methylcephem compound or 3-fluorinated methylcephem compound itself is difficult to synthesize. ##STR4##
JP-A-36690/1977 discloses a process wherein a 3-hydroxymethylcephem derivative serving as the starting material is reacted with an alcohol with addition of an activating agent such as trifluoroacetic anhydride, whereas since the 3-hydroxymethylcephem derivative is used as the material, the process yields a large amount of lactone compound as a by-product through an intramolecular cyclization reaction if a compound other than 4-position carboxylic acids is used, and is therefore not an appropriate process. Moreover, the process is not useful practically because at least two equivalents of the expensive activating agent is required relative to the starting material. ##STR5##
JP-A-49790/1990, JP-A-131181/1989 and JP-A-96091/1983 disclose a process for reacting a boric acid alkyl ester or alcohol with a 3-acyloxymethylcephem compound serving as the starting material in the presence of a Lewis acid. Similarly a report has been made on this reaction of alcohol as conducted in the presence of a Lewis acid and boron trifluoride compound. Presumably, however, difficulties will be encountered in industrially practicing these processes because of the necessity of using a large quantity of Lewis acid, or the need to use the boron compound which is expensive. ##STR6##
JP-A-163387/1984 discloses a process wherein this reaction is conducted with use of a sulfonic acid, but the yield is low to render the process infeasible. Although a report has been made on a process wherein the acetoxy group is iodized first, followed by a reaction with an alcohol (JP-A-192392/1982), the process requires a large amount of an iodine reagent and is difficult to practice on an industrial scale.
A report is also made on a process wherein the hydroxyl group of a 3-hydroxymethylcephem compound is alkylated with a diazomethane compound (JP-A-10873/1975). However, this process is far from being practical because of the need to use the diazo compound which is harmful to the human body and very hazardous. ##STR7##
Thus, various processes have been developed in view of the low reactivity of alkyl alcohols, but none of them are practically useful, and it has been desired to develop more suitable processes.
An object of the present invention is overcome the drawbacks of the conventional processes described and to provide a process for producing the desired 3-alkoxymethylcephem derivative in a high yield and with a high purity.